The goal of the proposed project is to define the synergistic roles of presenilins (PS1 and PS2) in cortical development and Notch signaling. Our previous studies of the PS1-null mouse revealed a role for PS1 in early neurogenesis and the regulation of Notch signaling. The perinatal lethality and the cerebral hemorrhage associated with PS1/- mice preclude a complete study of PS1 function in neuronal migration and cortical layer formation during later embryonic and postnatal stages. Furthermore, the early embryonic lethality (about 9) of the PS1PS2 -/-mice prevents the investigation of the role of both presenilins (PS) in cortical development and Notch signaling. We have therefore developed a viable PS1 conditional knockout (PS1cKO) mouse, in which Psi1 function is selectively eliminated in neural progenitor cells beginning at E9 and subsequently in the entire neuronal and glial populations. The PS1 cKO mouse allows us to generate a double cKO (PS1cKO; PS2-/-) lacking both PS in neural progenitor cells. Analysis of the PS1 single and PS1/PS2 double cKO mice will elucidate the role of PS1 and PS2 in neurogenesis, neuronal migration and Notch signaling during development. The significance of the proposed study is our characterization of the effects of partial and complete loss of PS function in vivo, the results of which would be applicable to the use of PS as therapeutic targets for anti-amyloidogenic therapy.